Abstract:In the present study, the role of antiperipheral nerve myelin antibody (anti-PNM Ab) in demyelination by generating the terminal attack complex (C5b-9) of complement was explored in patients with Guillain-Barre syndrome (GBS) and other demyelinating neuropathies. The presence in serum of SC5b-9, an inactive C5b-9 containing S protein, was assessed quantitatively by enzyme-linked immunosorbent assay using an antibody (Ab) to neoantigens expressed on C9 when complexed with C5b-8 or after tubular polymerization. … Show more
“…A large number of other complement-mediated disorders are known, and in many situations indications were found for the importance of the MAC. They include inflammation caused by trauma (49), rheumatoid arthritis (50), macular degeneration (51,52), hemolytic anemias (53,54), nephritis (55,56), and demyelinating neuropathies such as multiple sclerosis and Guillain-Barré syndrome (57,58). In rodent models, MAC formation increased the severity of rheumatoid arthritis, whereas a CD59 derivative decreased it (59,60).…”
Background: The C5b-6 complex triggers assembly of the Membrane Attack Complex. Results: The structure of C5b-6 at 4.2 Å resolution allowed an atomic model to be built. Conclusion: C5b is stabilized by an interdomain linker of C6 and N-terminal elements that simultaneously engage N-and C-terminal elements. Significance: In stabilizing C5b, C6 must change its conformation so that it becomes "primed" for initiating MAC assembly.
“…A large number of other complement-mediated disorders are known, and in many situations indications were found for the importance of the MAC. They include inflammation caused by trauma (49), rheumatoid arthritis (50), macular degeneration (51,52), hemolytic anemias (53,54), nephritis (55,56), and demyelinating neuropathies such as multiple sclerosis and Guillain-Barré syndrome (57,58). In rodent models, MAC formation increased the severity of rheumatoid arthritis, whereas a CD59 derivative decreased it (59,60).…”
Background: The C5b-6 complex triggers assembly of the Membrane Attack Complex. Results: The structure of C5b-6 at 4.2 Å resolution allowed an atomic model to be built. Conclusion: C5b is stabilized by an interdomain linker of C6 and N-terminal elements that simultaneously engage N-and C-terminal elements. Significance: In stabilizing C5b, C6 must change its conformation so that it becomes "primed" for initiating MAC assembly.
“…The increased C3 uptake in active phase of DM, but not in the chronic form or the controls, suggests that the high rate of complement activation may be responsible for the formation of a large number of activated early components. Whether C3 uptake is also increased in other complement-mediated neuromuscular diseases, such as Guillain-Barre syndrome (33) or myasthenia gravis where IVIG is also effective (23,34), is not known.…”
“…Antibody binding to target membranes results in complement activation with membrane attack complex (MAC) pore formation (Koski et al, 1987;Acosta et al, 1996). Our studies on antidisialosyl ganglioside Ab binding to presynaptic NMJ gangliosides indicate that uncontrolled calcium influx through MAC pores triggers massive neurotransmitter release with electrophysiological failure and calpain-mediated disintegration of the presynaptic axon Bullens et al, 2000;O'Hanlon et al, 2001O'Hanlon et al, , 2003Halstead et al, 2004).…”
Anti-GD1a ganglioside antibodies (Abs) are the serological hallmark of the acute motor axonal form of the post-infectious paralysis, Guillain-Barré syndrome. Development of a disease model in mice has been impeded by the weak immunogenicity of gangliosides and the apparent resistance of GD1a-containing neural membranes to anti-GD1a antibody-mediated injury. Here we used mice with altered ganglioside biosynthesis to generate such a model at motor nerve terminals. First, we bypassed immunological tolerance by immunizing GD1a-deficient, -1,4-N-acetylgalactosaminyl transferase knock-out mice with GD1a ganglioside-mimicking antigens from Campylobacter jejuni and generated high-titer anti-GD1a antisera and complement fixing monoclonal Abs (mAbs). Next, we exposed ex vivo nerve-muscle preparations from GD1a-overexpressing, GD3 synthase knock-out mice to the anti-GD1a mAbs in the presence of a source of complement and investigated morphological and electrophysiological damage. Dense antibody and complement deposits were observed only over presynaptic motor axons, accompanied by severe ultrastructural damage and electrophysiological blockade of motor nerve terminal function. Perisynaptic Schwann cells and postsynaptic membranes were unaffected. In contrast, normal mice were not only unresponsive to immunization with GD1a but also resistant to neural injury during anti-GD1a Ab exposure, demonstrating the central role of membrane antigen density in modulating both immune tolerance to GD1a and axonal susceptibility to anti-GD1a Abmediated injury. Identical paralyzing effects were observed when testing mouse and human anti-GD1a-positive sera. These data indicate that anti-GD1a Abs arise via molecular mimicry and are likely to be clinically relevant in injuring peripheral nerve axonal membranes containing sufficiently high levels of GD1a.
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